Animal experiment:

MK-801 is dissolved in saline and administered intraperitoneally (i.p.) in a within subjects dosing paradigm in order of increasing dose (0.1, 0.2, and 0.3 mg/kg). IC87201 (1, 4 and 10 mg/kg) and ZL006 (10 mg/kg) are dissolved in a vehicle containing 3% DMSO with the remaining 97% comprised of 1:1:18 of emulphor:ethanol:0.9% NaCl. Active compounds are compared with equivalent volumes of the appropriate vehicle in each case. MK-801, IC87201, and ZL006 are administered 30 min prior to behavioral testing. All drugs are administered intraperitoneally (i.p.) in a volume of 1 mL/kg[2].

IC87201, an inhibitor of PSD95-nNOS protein-protein interactions, suppresses NMDAR-dependent NO and cGMP formation.

IC87201 (500-1800 μM) does not inhibit any of the probe-PDZ interactions involving PDZ1, PDZ2, PDZ3 of PSD-95 or nNOS-PDZ, or bind the canonical PDZ ligand binding sites. IC87201 binds to the β-finger of nNOS-PDZ and allosterically inhibits the nNOS-PDZ/PSD-95-PDZ interactions. IC87201 shows high degree of fluorescence-based artefactual signal when using TAMRA-nNOS as probe[1]. IC87201 (20 μM) suppresses NMDA-stimulated cGMP formation relative to vehicle, in cultured hippocampal neurons[2]. IC87201 (10 and 100 nM) attenuats NMDA/glycine-induced decreases in neurite outgrowth. IC87201 dose-dependently reduces NMDA-induced cGMP production in primary hippocampal neurons (DIV 14-21) with an IC50 of 2.7 μM. IC87201 increases the number of branches at 10-30 μM when compared to control-treated neurons[3].

IC87201 (1, 4 and 10 mg/kg, i.p.) does not produce impairment in either spatial working memory or source memory[2]. IC87201 (1 mg/kg) is effective in treating NMDA-induced thermal hyperalgesia in mice, with a corresponding peak plasma level of 55 ng/mL (or 0.2 μM)[3].

[1]. Bach A, et al. Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions. Sci Rep. 2015 Jul 16;5:12157. [2]. Smith AE, et al. Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors. Behav Brain Res. 2016 May 15;305:23-9. [3]. Doucet MV, et al. Small-molecule inhibitors at the PSD-95/nNOS interface protect against glutamate-induced neuronal atrophy in primary cortical neurons. Neuroscience. 2015 Aug 20;301:421-38.